title: Eradication of solid tumors using histone deacetylase inhibitors combined with immune-stimulating antibodies.
abstract: Histone deacetylase inhibitors (HDACi) have been successfully used as monotherapies for the treatment of hematological malignancies; however, the single agent effects of HDACi against solid tumors are less robust. Using preclinical models of lymphoma, we have recently demonstrated that HDACi induce tumor cell-specific apoptosis and that this is essential for the therapeutic effects of these agents. Herein, we demonstrate that HDACi can be combined with immune-activating antibodies designed to promote the function of antigen-presenting cells (APCs) and enhance proliferation and survival of cytotoxic T cells (CTL) to stimulate a host antitumor immune response resulting in eradication of established solid tumors. This unique combination therapy was dependent on tumor cell apoptosis mediated by HDACi that stimulated the uptake of dead tumor cells by APCs. Tumor eradication was mediated by CD8(+) CTL that used perforin as the key immune effector molecule. This combination therapy was well tolerated and induced long-term immunological antitumor memory capable of mediating spontaneous tumor eradication upon rechallenge. These studies indicate that the ability of HDACi to mediate subtherapeutic levels of tumor cell apoptosis can be exploited by combining with antibodies that augment host antitumor immune responses to mediate robust and prolonged eradication of solid tumors.
authors.affiliation: Cancer Therapeutics Program, The Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, VIC 3002, Australia.
authors.forename: Ailsa J
authors.initials: AJ
authors.lastname: Christiansen
authors.forename: Alison
authors.initials: A
authors.lastname: West
authors.forename: Kellie-Marie
authors.initials: KM
authors.lastname: Banks
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Haynes
authors.forename: Michele W
authors.initials: MW
authors.lastname: Teng
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: Ricky W
authors.initials: RW
authors.lastname: Johnstone
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000938:Antigen-Presenting Cells / Q000276:immunology; D003131:Combined Modality Therapy; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D000077337:Vorinostat
chemical_list: D000911:Antibodies, Monoclonal; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat